Skewed mutational spectrum of RET proto-oncogene Exon10 in Iranian patients with medullary thyroid carcinoma

Abstract

Thyroid cancer is the most common endocrine malignant tumor. Medullary thyroid carcinoma (MTC) is an aggressive tumor arising from calcitonin-producing parafollicular cells. MTC has autosomal dominant inheritance and accounts for 5-10 % of all thyroid cancers. It occurs in hereditary (25 %, hMTC) and sporadic (75 %, sMTC) forms. Gain-of-function mutations in the REarranged during transfection (RET) proto-oncogene have been identified in 98 % of hMTC and 50 % of sMTC. The aim of this investigation was to identify mutation(s) in the much conserved RET exon10 in Iranian MTC patients. We started screening patients with MTC for RET in 2001. This study included 347 individuals (154 with sMTC, 38 with FMTC, 8 with multiple endocrine neoplasia type 2A [MEN2A], 3 with MEN2B, and 3 with pheochromocytoma; 207 index cases and 140 relatives). Germline mutation screening of RET exon10 was performed with PCR-DNA sequencing. A total of 14 missense mutations (10 mutations in men and 4 in women) were identified in cysteine codons 611, 618, and 620 (exon10) in 11 patients and three first-degree relatives as follows: four C611Y (three with FMTC and one relative), one C618R (FMTC), one C618S (sMTC), one C620G (sMTC), four C620R (one with FMTC and three with sMTC), and three C620F (one with FMTC and two relatives). In the present study, six different mutations were identified in exon10 of RET in 14 patients with sMTC and FMTC that were restricted to codons 611, 618, and 620, but not in codon 609. This data showed a skewed pattern of RET exon10 mutation compared to other populations. No mutation was found for MEN2A, MEN2B, and pheochromocytoma in exon10 in this population. In the most common mutations in exon10, the FMTC and sMTC patients were C611Y and C620R, respectively.

Rare RET Variant p.D707E in a Chinese Pedigree with Hereditary Medullary Thyroid Carcinoma

“…(3) The single-nucleotide polymorphisms (SNP) G691S in exon 11 (rs1799939), S904S in exon 15 (rs1800863), and rs2075912 and rs2565200 in the 3 ′ -untranslated region of the RET proto-oncogene are in complete linkage disequilibrium (D' = 1, r 2 = 1); no correlation of these SNP and MTC was observed in this pedigree. (4) No hot-spot mutation of the RET protooncogene was detected in this pedigree. We drew the conclusion that the heterozygous nonsynonymous variant p.D707E in the RET proto-oncogene is rare, but it is a risk factor for hereditary MTC.…”

“…HMTC is an autosomal dominant genetic disease with 3 subtypes: multiple endocrine neoplasia type 2A (MEN 2A; 55-60%), multiple endocrine neoplasia type 2B (MEN 2B; 5-10%) and familial MTC (35-40%). MEN 2A is generally accompanied by adrenal pheochromocytoma (PHEO) and/or hyperparathyroidism, and the onset age usually ranges from 20 to 30 years [3][4][5] .…”

Efficacy of vandetanib in the treatment of medullary thyroid cancer: literature review and case report

“…Активация протоонкогена RET при опухолях щитовидной железы может происходить из-за точечных мутаций или слияний с другими генами [22]. Активирующая мутация RET при наследственных формах МРЩЖ наблюдается в 98 % случаев, а при спорадическом МРЩЖ -в 50 % [23]. Протеин RET состоит из внеклеточного домена, ответственного за связывание с лигандом, и внутриклеточного домена.…”

Cabozantinib in Thyroid Cancer

“…Germline or somatic point mutations in RET are the main responsible for MTC [56]. Particularly, activating mutations of RET have been found in almost all cases of hereditary MTC and about 50% of sporadic MTC [57]. The substitution of methionine by threonin at codon 918 (M918T) is the most common mutation in sporadic MTC [58]; also somatic RET mutations are linked to advanced MTC at diagnosis and a worse prognosis [59].…”